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Isoflavone Extracts Enhance the Effect of Epidermal Growth Factor

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Isoflavone Extracts Enhance the Effect of Epidermal Growth Factor ANTICANCER RESEARCH 36 : 5827-5834 (2016) doi:10.21873/anticanres.11167 Isoflavone Extracts Enhance the Effect of Epidermal Growth Factor Receptor Inhibitors in NSCLC Cell Lines RITA AMBROSIO 1* , MARIA NEVE OMBRA 2* , CESARE GRIDELLI 1, GIANLUCA PICARIELLO 2, MICHELE DI STASIO 2 and MARIA G. VOLPE 2 1Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy; 2Institute of Food Sciences, National Research Council, Avellino, Italy Abstract. Aim: We investigated the effects of the NSCLCs (1-3). Irreversible inhibitors such as afatinib and pharmacological inhibition in vitro of epidermal growth AZD9291 constitute second- and third-generation EGFR factor receptor (EGFR) in combination with isoflavones. inhibitors. Progression-free survival (PFS) of patients with Materials and Methods: Four anticancer drugs (erlotinib, EGFR mutation receiving gefitinib, erlotinib or afatinib is gefitinib, afatinib and AZD9291) were combined with soy improved when compared with standard chemotherapy, as and red clover isoflavone extracts and used in cellular demonstrated with randomized trials (4). Unfavorably, TKI proliferation assays. The antitumor activity of inhibitors therapies may become ineffective due to acquired resistance alone and in combination with isoflavone extracts was that may develop after a duration of response of ~10 months compared on three non-small cell lung cancer (NSCLC) cell up to 1 year (5, 6). A secondary mutation in exon 20 of lines with affiant EGFR genotype: A549 (EGFR wt); H1795 EGFR within the residue at position 790 inducing a (EGFR T790M); HCC827 (EGFR del E746-A750). Results: threonine to methionine substitution (T790M) was Combined treatment with extracts significantly enhanced the determined as the first cause of resistance identified on a antiproliferative activity of all inhibitors against these cell genetic basis. T790M causes resistance through changes in lines. Bioactive compounds of extracts may synergize the adenosine triphosphate (ATP) affinity because T790M antitumor efficacy of the inhibitors. Conclusion: To date, as mutation restores the ATP affinity of the kinase, re- far as we are aware, this is the first report of the combined establishing ATP as the favored substrate rather than the effect of isoflavone extracts and EGFR inhibitors on human administered TKI (7). Second-generation EGFR TKIs, such NCSLC cell growth. Sequential treatment with these drugs afatinib, form irreversible covalent bonds with EGFR and are combined with isoflavones may represent the basis for a new potentially effective in vitro against cells with EGFR therapeutic approach. T790M. Third-generation EGFR TKIs, such as AZD9291/are being developed to overcome resistance to first- and second- Epidermal growth factor receptor (EGFR)-targeted therapies generation EGFR TKIs. In preclinical studies, AZD9291 was using small molecules, such as tyrosine kinase inhibitors active both in vitro and in vivo against cell lines and murine (TKI) have recently been approved for non-small cell lung models harboring the EGFR T790M mutation (8). Very cancer (NSCLC). In particular, two EGFR tyrosine kinase promising results from an ongoing phase I study on inhibitors (TKI), gefitinib (ZD1839, Iressa) and erlotinib AZD9291 have been reported (9). (OSI774, Tarceva), represent the first generation of Recently, natural dietary compounds have captured molecular-targeted agents developed for the treatment of attention because of their synergistic effects with anticancer drugs against various types of cancer. Natural phytochemicals may accomplish their antitumoral effect through targeting diverse cancer cell signaling pathways, *These Authors contributed equally to this study. giving rise to cell-cycle block and apoptosis, or regulating antioxidant status and detoxification (10). Much evidence Correspondence to: Dr Maria Grazia Volpe, Institute of Food has shown that isoflavones exert their pleiotropic effects on Sciences – CNR, Via Roma, 64, 83100 Avellino, AV, Italy. Tel: +39 0825299411, Fax: +39 0825781585, e-mail: [email protected] cancer cells by interfering in cellular signaling pathways including nuclear factor kappa-light-chain-enhancer of Key Words: Isoflavones, non-small cell lung cancer, antiproliferative activated B-cells, serine/threonine kinase, mitogen-activated activity, tyrosine kinase inhibitors. protein kinase, and p53. 0250-7005/2016 $2.00+.40 5827 ANTICANCER RESEARCH 36 : 5827-5834 (2016) Isoflavones are principally recovered in members of the CA, USA). Total flavonoid content was expressed as mg catechin Leguminosae family (11). Genistein is the most extensively equivalents (CAE, in mg) per gram of dry material. All samples analyzed flavonoid, it is involved in numerous biological were analyzed in triplicates. actions with potential beneficial effects, rightly becoming a Determination of antioxidant activity. The 2,2-diphenyl-1- focus for research (12). Genistein is also a well-known TKI picrylhydrazyl (DPPH) free radical-scavenging activity assay was and induces apoptosis in several types of cancer, such as performed as described by Rostagno et al. (15). Briefly 20 μl of lymphoma, leukemia, breast, prostate, head and neck, extract (1 mg/ml) in absolute ethanol was added to 180 μl of DPPH pancreatic and lung cancer (13). reagent in a 96-well plate. The absorbance was measured at 517 nm In the present study, the effect of gefitinib, erlotinib, after 90 min, with a microplate reader (Biotek). Experiments were afatinib and AZD9291 (selective EGFR TKIs) combined performed in triplicates. The results were expressed as percentage with isoflavones from soy and red clover was assayed on a inhibition (I%), which was calculated using the following formula: panel of NSCLC cell lines by using 3-(4,5-dimethylthiazol- I%=[(A DPPH −A Sample )/A DPPH ]×100 2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assays. Our aim was to evaluate in vitro whether these where: A DPPH is the absorbance of the control DPPH at time t=0’ isoflavone extracts synergize with TKIs to inhibit NSCLC and cell growth. ASample is the absorbance of the sample after time t=90’. Materials and Methods High-performance liquid chromatography (HPLC) analysis of isoflavones. Isoflavone extracts were analyzed using a modular Samples and extraction. Fresh faba beans ( Vicia faba ), peas ( Pisum HPLC system (1100 Series; Agilent Technology, Palo Alto, CA, USA) equipped with a 250×2.0 mm, 4 μm particle diameter, sativum ), ordinary beans ( Phaseolus vulgare ) and soybean ( Glycine ® max ) seeds were purchased at a local market, while dried red clover Jupiter C18 reversed-phase column (Phenomenex, Torrance, CA, (Trifolium pretense L.) was obtained at a herbalist’s shop. Standards USA) that was maintained at 37˚C in a thermostatic oven. of genistin, glycitin, daidzin, biochanin A and formonotenin were Separations were carried out at a 0.2 ml/min constant flow rate, purchased from Sigma-Aldrich (St. Louis, MO, USA). Genistein, applying a 5-65% linear gradient of eluent B (acetonitrile/0.1% glycitein and daidzein aglycones were obtained by acid hydrolysis trifluoroacetic acid) in 60 min, following 5 min of isocratic elution (using 3.4 N HCl at 50˚C for 200 min) of the corresponding β- at 5% B. Eluent A was 0.1% trifluoroacetic acid in HPLC-grade glucosides, according to Chiang et al. (14), with slight water. A diode array detector was used to record UV-Vis spectra modifications. every 2 s in the 190-650 nm range. The HPLC separations were A protocol for the extraction of phenolic compounds was adapted monitored recording at the following wavelengths: λ=254, 280, 320 from Rostagno et al. (15). Briefly, 0.5 g of the dry sample was and 360 nm; and elaborated with the HPLC ChemStation software suspended in 5 ml of 50% ethanol (v/v) and ultrasonicated for 20 vers. A.07.01 (Agilent Technology) furnished with the min at 60˚C. The suspension was centrifuged for 10 min at ~2500×g chromatographer. and the supernatant was recovered. The pellet was re-extracted for 12 hours with an additional 5 ml of solvent and centrifuged. The Cell culture. Three NSCLC cell lines with different EGFR mutation two supernatants were combined and stored in a freezer at −20˚C status and sensitivity to EGFR TKIs were used: HCC827 (del E746- for subsequent analysis (16, 17). A750), NCI-H1975 (T790M), and A549 (wild-type). Cells were obtained from the American Type Culture Collection (ATCC; Determination of total phenolic compounds. The total polyphenol Manassas, VA, USA) and maintained in ATCC-specified growth content in the extracts was determined using the Folin-Ciocolteau medium. method (18). Fifty microliters of dried bean, pea, red clover and soya extracts were combined to 3 ml with distilled water, 250 μl of EGFR inhibitors . Erlotinib and gefitinib were purchased from Folin and 750 μl of 7% (w/v) Na 2CO 3. After 8 min, 950 ml of Genentech (South San Francisco, CA, USA); AstraZeneca (London, distilled water was added. Samples were left for 2 h at room UK) commercial suppliers, respectively. Afatinib was provided by temperature in the dark and the absorbance at 765 nm was then Boehringher Ingelheim (Ingelheim Am Rhein, Rheinland-Pfalz, determined spectrophotometrically microplate reader, (Cary 50 Germany), AZD9291 by AstraZeneca. Stock solutions of TKIs were MPR; Varian, LAB X, LA Jolla, CA, USA). Total polyphenol prepared in dimethyl sulfoxide at a concentration of 10 mmol/l and content was expressed as gallic acid equivalents (GAE, in mg) per maintained at −20˚C. Drugs were diluted to
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